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PMID: 

Life Sci. 2020 Mar 23:117583. Epub 2020 Mar 23. PMID: 32217117

Abstract Title: 

COVID-19: Melatonin as a potential adjuvant treatment.

Abstract: 

This article summarizes the likely benefits of melatonin in the attenuation of COVID-19 based on its putative pathogenesis. The recent outbreak of COVID-19 has become a pandemic with tens of thousands of infected patients. Based on clinical features, pathology, the pathogenesis of acute respiratory disorder induced by either highly homogenous coronaviruses or other pathogens, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response very likely contribute to COVID-19 pathology. This leads to a cytokine storm and subsequent progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and often death. Melatonin, a well-known anti-inflammatory and anti-oxidative molecule, is protective against ALI/ARDS caused by viral and other pathogens. Melatonin is effective in critical care patients by reducing vessel permeability, anxiety, sedation use, and improving sleeping quality, which might also be beneficial for better clinical outcomes for COVID-19 patients. Notably, melatonin has a high safety profile. There is significant data showing that melatonin limits virus-related diseases and would also likely be beneficial in COVID-19 patients. Additional experiments and clinical studies are required to confirm this speculation.

PMID: 

J Immunol. 2016 Mar 1 ;196(5):2119-31. Epub 2016 Jan 29. PMID: 26826239

Abstract Title: 

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner.

Abstract: 

Demethylation of CpG motifs in the Foxp3 intronic element, conserved noncoding sequence 2 (CNS2), is indispensable for the stable expression of Foxp3 in regulatory T cells (Tregs). In this study, we found that vitamin C induces CNS2 demethylation in Tregs in a ten-eleven-translocation 2 (Tet2)-dependent manner. The CpG motifs of CNS2 in Tregs generated in vitro by TGF-β (iTregs), which were methylated originally, became demethylated after vitamin C treatment. The conversion of 5-methylcytosin into 5-hydroxymethylcytosin was more efficient, and the methyl group from the CpG motifs of Foxp3 CNS2 was erased rapidly in iTregs treated with vitamin C. The effect of vitamin C disappeared in Tet2(-/-) iTregs. Furthermore, CNS2 in peripheral Tregs in vivo, which were demethylated originally, became methylated after treatment with a sodium-dependent vitamin C transporter inhibitor, sulfinpyrazone. Finally, CNS2 demethylation in thymic Tregs was also impaired in Tet2(-/-) mice, but not in wild type mice, when they were treated with sulfinpyrazone. Collectively, vitamin C was required for the CNS2 demethylation mediated by Tet proteins, which was essential for Foxp3 expression. Our findings indicate that environmental factors, such as nutrients, could bring about changes in immune homeostasis through epigenetic mechanisms.

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PMID: 

Front Cell Infect Microbiol. 2017 ;7:43. Epub 2017 Feb 22. PMID: 28275584

Abstract Title: 

Vitamin C Pretreatment Enhances the Antibacterial Effect of Cold Atmospheric Plasma.

Abstract: 

Bacterial biofilms are three-dimensional structures containing bacterial cells enveloped in a protective polymeric matrix, which renders them highly resistant to antibiotics and the human immune system. Therefore, the capacity to make biofilms is considered as a major virulence factor for pathogenic bacteria. Cold Atmospheric Plasma (CAP) is known to be quite efficient in eradicating planktonic bacteria, but its effectiveness against biofilms has not been thoroughly investigated. The goal of this study was to evaluate the effect of exposure of CAP against mature biofilm for different time intervals and to evaluate the effect of combined treatment with vitamin C. We demonstrate that CAP is not very effective against 48 h mature bacterial biofilms of several common opportunistic pathogens:, and. However, if bacterial biofilms are pre-treated with vitamin C for 15 min before exposure to CAP, a significantly stronger bactericidal effect can be obtained. Vitamin C pretreatment enhances the bactericidal effect of cold plasma by reducing the viability from 10 to 2% inbiofilm, 50 to 11% in, and 61 to 18% inbiofilm. Since it is not feasible to use extended CAP treatments in medical practice, we argue that the pre-treatment of infectious lesions with vitamin C prior to CAP exposure can be a viable route for efficient eradication of bacterial biofilms in many different applications.

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PMID: 

J Immunol. 2005 Jun 15 ;174(12):7633-44. PMID: 15944264

Abstract Title: 

Inhibition of NF-kappa B and oxidative pathways in human dendritic cells by antioxidative vitamins generates regulatory T cells.

Abstract: 

Dendritic cells (DCs) are central to T cell immunity, and many strategies have been used to manipulate DCs to modify immune responses. We investigated the effects of antioxidants ascorbate (vitamin C) and alpha-tocopherol (vitamin E) on DC phenotype and function. Vitamins C and E are both antioxidants, and concurrent use results in a nonadditive activity. We have demonstrated that DC treated with these antioxidants are resistant to phenotypic and functional changes following stimulation with proinflammatory cytokines. Following treatment, the levels of intracellular oxygen radical species were reduced, and the protein kinase RNA-regulated, eukaryotic translation initiation factor 2alpha, NF-kappaB, protein kinase C, and p38 MAPK pathways could not be activated following inflammatory agent stimulation. We went on to show that allogeneic T cells (including CD4(+)CD45RO, CD4(+)CD45RA, and CD4(+)CD25(-) subsets) were anergized following exposure to vitamin-treated DCs, and secreted higher levels of Th2 cytokines and IL-10 than cells incubated with control DCs. These anergic T cells act as regulatory T cells in a contact-dependent manner that is not dependent on IL-4, IL-5, IL-10, IL-13, and TGF-beta. These data indicate that vitamin C- and E-treated DC might be useful for the induction of tolerance to allo- or autoantigens.

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PMID: 

J Leukoc Biol. 2007 May ;81(5):1236-44. Epub 2007 Jan 30. PMID: 17264304

Abstract Title: 

Ascorbate deficiency results in impaired neutrophil apoptosis and clearance and is associated with up-regulation of hypoxia-inducible factor 1alpha.

Abstract: 

Some cells, including neutrophils, accumulate high intracellular ascorbate concentrations, which suggests that they have an important function in these cells. In this study we have used L-gulono-gamma-lactone oxidase (Gulo)-/- mice, which are unable to synthesize ascorbate, to generate ascorbate-deficient neutrophils and have used these to investigate the effect of ascorbate on neutrophil function. Peritoneal neutrophils from ascorbate-deficient animals had normal morphology and respiratory burst activity but failed to undergo spontaneous apoptosis, determined by morphology and the surface expression of phosphatidylserine. Initially, there was increased cell survival, but death eventually occurred by necrosis within 48 h. Neutrophils persisted in thioglycollate-induced inflammation in Gulo-/- mice with the later appearance of necrotic cells, suggesting that apoptosis was also affected in vivo. Also, ascorbate-deficient neutrophils were not recognized by macrophages in an in vitro assay for phagocytosis, providing further evidence for defective apoptosis and clearance. Neutrophils from Gulo-/- mice had elevated levels of hypoxia-inducible factor (HIF)-1alpha, a transcription factor regulated by Fe2+-dependent hydroxylases which require ascorbate for optimal activity. HIF-1alpha has been shown previously to inhibit neutrophil apoptosis under hypoxic conditions. Our results suggest that in ascorbate deficiency, up-regulation of HIF-1alpha blocks neutrophil apoptosis under normoxic conditions and that this represents a novel and important function for vitamin C in inflammatory cells.

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PMID: 

IUBMB Life. 2019 04 ;71(4):487-494. Epub 2018 Nov 30. PMID: 30501009

Abstract Title: 

Regulatory role of vitamin E in the immune system and inflammation.

Abstract: 

Vitamin E, a potent lipid-soluble antioxidant, found in higher concentration in immune cells compared to other cells in blood, is one of the most effective nutrients known to modulate immune function. Vitamin E deficiency has been demonstrated to impair normal functions of the immune system in animals and humans, which can be corrected by vitamin E repletion. Although deficiency is rare, vitamin E supplementation above current dietary recommendations has been shown to enhance the function of the immune system and reduce risk of infection, particularly in older individuals. The mechanisms responsible for the effect of vitamin E on the immune system and inflammation have been explored in cell-based, pre-clinical and clinical intervention studies. Vitamin E modulates T cell function through directly impacting T cell membrane integrity, signal transduction, and cell division, and also indirectly by affecting inflammatory mediators generated from other immune cells. Modulation of immune function by vitamin E has clinical relevance as it affects host susceptibility to infectious diseases such as respiratory infections, in addition to allergic diseases such as asthma. Studies examining the role of vitamin E in the immune system have typically focused onα-tocopherol; however, emerging evidence suggests that other forms of vitamin E, including other tocopherols as well as tocotrienols, may also have potent immunomodulatory functions. Future research should continue to identify and confirm the optimal doses for individuals at different life stage, health condition, nutritional status, and genetic heterogeneity. Future research should also characterize the effects of non-α-alpha-tocopherol vitamin E on immune cell function as well as their potential clinical application. © 2018 IUBMB Life, 71(4):487-494, 2019.

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PMID: 

Nutrients. 2018 Nov 1 ;10(11). Epub 2018 Nov 1. PMID: 30388871

Abstract Title: 

The Role of Vitamin E in Immunity.

Abstract: 

Vitamin E is a fat-soluble antioxidant that can protect the polyunsaturated fatty acids (PUFAs) in the membrane from oxidation, regulate the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and modulate signal transduction. Immunomodulatory effects of vitamin E have been observed in animal and human models under normal and disease conditions. With advances in understating of the development, function, and regulation of dendritic cells (DCs), macrophages, natural killer (NK) cells, T cells, and B cells, recent studies have focused on vitamin E's effects on specific immune cells. This review will summarize the immunological changes observed with vitamin E intervention in animals and humans, and then describe the cell-specific effects of vitamin E in order to understand the mechanisms of immunomodulation and implications of vitamin E for immunological diseases.

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PMID: 

Expert Opin Biol Ther. 2017 12 ;17(12):1539-1551. Epub 2017 Sep 14. PMID: 28905653

Abstract Title: 

Induction of cellular and molecular Immunomodulatory pathways by vitamin E and vitamin C.

Abstract: 

Vitamins E and C are well known small molecules that have been used to maintain health for decades. Recent studies of the cellular and molecular pathways leading to immunomodulation by these molecules have been of interest, as have their anti-oxidant properties and signal transduction pathways for curing or improving infectious diseases and cancer. Areas covered: Herein, the authors provide a definition and the structural classification of vitamins E and C and how these molecules influence cellular function. The studies include in vitro, ex vivo and in vivo studies in animal models as well as clinical trials. The authors give particular focus to the scientifically factual and putative roles of these molecules in innate and adaptive immunomodulation and prevention or cure of diseases. Expert opinion: The antioxidant properties of vitamins E and C are well studied. However, whether there is a link between their antioxidant and immunomodulation properties is unclear. In addition, there is a strong, albeit putative, prevailing notion that vitamin C can prevent or cure infectious diseases or cancer. Presently, while there is proven evidence that vitamin E possesses immunomodulatory properties that may play a positive role in disease outcomes, this evidence is less available for vitamin C.

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PMID: 

Int Immunopharmacol. 2013 Feb ;15(2):395-9. Epub 2012 Dec 20. PMID: 23261366

Abstract Title: 

Immunomodulatory effect of pleuran (β-glucan from Pleurotus ostreatus) in children with recurrent respiratory tract infections.

Abstract: 

OBJECTIVES: Recurrent respiratory tract infections (RRTIs) represent a very important problem in daily clinical practice because of their significant contribution to morbidity in children. Several natural nutritional supplements have been used in the prevention of RRTIs, but the clinical efficacy of only a few preparations is supported by scientific evidence.MATERIALS AND METHODS: In a double-blind, placebo-controlled, randomised, multicentre study, we have observed a group of 175 children (aged 5.65± 2.39 years) with more than 5 respiratory infections that occurred during the 12 months prior to the beginning of the study. Children were randomised into an active group, treated with Imunoglukan P4H® syrup (with pleuran-β-glucan from Pleurotus ostreatus and vitamin C), or a placebo group (vitamin C only). During the 3 visits, within a 12-month period, questionnaires were completed, and blood samples were examined for immune parameters.RESULTS: In the active group, 36% of the children did not suffer from any respiratory infections throughout the treatment, compared to 21% in the placebo group (p

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PMID: 

Cochrane Database Syst Rev. 2013 Aug 8(8):CD005532. Epub 2013 Aug 8. PMID: 23925826

Abstract Title: 

Vitamin C for preventing and treating pneumonia.

Abstract: 

BACKGROUND: Pneumonia is one of the most common serious infections, causing two million deaths annually among young children in low-income countries. In high-income countries pneumonia is most significantly a problem of the elderly.OBJECTIVES: To assess the prophylactic and therapeutic effects of vitamin C on pneumonia.SEARCH METHODS: We searched CENTRAL 2013, Issue 3, MEDLINE (1950 to March week 4, 2013), EMBASE (1974 to April 2013) and Web of Science (1955 to April 2013).SELECTION CRITERIA: To assess the therapeutic effects of vitamin C, we selected placebo-controlled trials. To assess prophylactic effects, we selected controlled trials with or without a placebo.DATA COLLECTION AND ANALYSIS: Two review authors independently read the trial reports and extracted data.MAIN RESULTS: We identified three prophylactic trials which recorded 37 cases of community-acquired pneumonia in 2335 people. Only one was satisfactorily randomised, double-blind and placebo-controlled. Two trials examined military recruits and the third studied boys from"lower wage-earning classes"attending a boarding school in the UK during World War II. Each of these three trials found a statistically significant (80% or greater) reduction in pneumonia incidence in the vitamin C group. We identified two therapeutic trials involving 197 community-acquired pneumonia patients. Only one was satisfactorily randomised, double-blind and placebo-controlled. That trial studied elderly patients in the UK and found lower mortality and reduced severity in the vitamin C group; however, the benefit was restricted to the most ill patients. The other therapeutic trial studied adults with a wide age range in the former Soviet Union and found a dose-dependent reduction in the duration of pneumonia with two vitamin C doses. We identified one prophylactic trial recording 13 cases of hospital-acquired pneumonia in 37 severely burned patients; one-day administration of vitamin C had no effect on pneumonia incidence. The identified studies are clinically heterogeneous which limits their comparability. The included studies did not find adverse effects of vitamin C.AUTHORS' CONCLUSIONS: The prophylactic use of vitamin C to prevent pneumonia should be further investigated in populations who have a high incidence of pneumonia, especially if dietary vitamin C intake is low. Similarly, the therapeutic effects of vitamin C should be studied, especially in patients with low plasma vitamin C levels. The current evidence is too weak to advocate prophylactic use of vitamin C to prevent pneumonia in the general population. Nevertheless, therapeutic vitamin C supplementation may be reasonable for pneumonia patients who have low vitamin C plasma levels because its cost and risks are low.

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